June 11, 2014. One of several types of ligand-gated ion channel, the N-methyl-D-aspartate (NMDA) receptor transmits excitatory stimuli in the brain. When calcium flows through this channel, neural plasticity happens and learning and memory are facilitated. Alas, too much of this good thing leads to excitotoxicity that might cause neurodegeneration in diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. While widely accepted, all this is complex and visually murky. A paper in the May 30 Science affords the most detailed view of the intact NMDA receptor yet. Erkan Karakas and Hiro Furukawa of Cold Spring Harbor Laboratory, New York, used X-ray crystallography to peer at the arrangement of the receptor’s four subunits and their various domains. Their data confirm the previously predicted configuration of its subunits and suggest an explanation for why allosteric modulators have an impact on the regions furthest from the ion channel itself. Unravelling the minute details of this receptor will help researchers understand its complex function and how it might be better targeted by therapies, wrote the authors. Memantine, an NMDA receptor antagonist, is one of only four drugs approved for AD.

"The NMDA receptor is so important for disease, and there has been an enormous effort to design different compounds that bind to its various regions,” Furukawa told Alzforum. “This full-length structure will help us understand which parts of the NMDA receptors these compounds are binding."

Previous studies have visualized only bits and pieces of the receptor, because it has been difficult to express it in its entirety and in large enough quantities to perform crystallography. Karakas and Furukawa overcame these difficulties with genetic tweaks. They then crystallized NMDA receptors that were bound to two different agonists—glycine or L-glutamate—or the allosteric inhibitor ifenprodil. The scientists stabilized the heterotetramer by creating disulfide bonds between the four subunits. X-ray crystallography then revealed the atomic structure of the protein and interactions between the receptor’s four subunits, including both extracellular and transmembrane portions, at a resolution of 4 angstroms.

It turns out that the NMDA receptor looks a bit like a hot-air balloon. The extracellular amino terminal domain (ATD) and ligand-binding domain (LBD) form the balloon portion and the transmembrane domain makes up the basket. As previously predicted, the four subunits—two identical pairs—lie in a staggered arrangement akin to two white and two black squares that make a bigger square on a checkerboard. This is likely because of steric clashes in the ligand-binding domain that would occur if pairs butted up against each other, the authors wrote.

The scientists compared their new conquest to the AMPA receptor, whose structure had been solved previously (Sobolevsky et al., 2009). They saw that the close proximity of the NMDAR’s ATD, which binds allosteric modulators, and LBD, which controls channel opening, explains why allosteric modulators influence when the channel opens. In essence, structural changes from the ATD can be easily transmitted to the LBD. In the AMPA receptor, the ATD and LBD interact less to confer more of a Y-shape, and the ATD does not serve as a site for allosteric modulation.

Furukawa said that his team will solve the structures for different states of the ion channel when NMDA binds to various agonists, antagonists, and allosteric modulators. This should help researchers improve therapeutic compounds, including ifenprodil and memantine, which bind the ATD and channel pore, respectively. (Unlike memantine, ifenprodil is not a therapeutic.) It may even help in the design of new compounds, Furukawa told Alzforum.—Gwyneth Dickey Zakaib